The addition of dual PD-1 and LAG-3 inhibition with cemiplimab-rwlc and fianlimab to standard paclitaxel-based neoadjuvant chemotherapy resulted in improved pathologic complete response rates in patients with early-stage, high-risk ERBB2 (formerly HER2 or HER2/neu)-negative breast cancer, according to results from the ongoing phase II I-SPY2 trial. The benefit was reported to be particularly marked in those with an immune-positive signature, providing a potential biomarker of treatment response.
“Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response,” the investigators wrote. “Dual checkpoint blockade offers a potential strategy to further enhance efficacy.”
Isaacs et al reported their findings in JAMA Oncology, concluding that the combination warrants further evaluation in definitive trials.
Study Details
The multicenter platform trial—which has continuously enrolled patients with locally advanced, early-stage (II or III) breast cancer at high risk of recurrence since 2010—is evaluating multiple therapies in parallel, with investigational agents and combinations added to a backbone of and compared against standard-of-care neoadjuvant chemotherapy.
The present analysis included 76 evaluable patients in the intervention group and 350 evaluable patients from the historical control population, all with ERBB2-negative disease. Both groups received weekly paclitaxel for 12 weeks, followed by doxorubicin and cyclophosphamide and then surgery. During paclitaxel treatment, the intervention group additionally received four doses of cemiplimab plus fianlimab every 3 weeks.
The primary endpoint was pathologic complete response. Treatments graduated upon reaching an 85% Bayesian probability of success in a subtype-specific phase III trial. The investigators also assessed pathway-specific biomarkers as predictors of treatment response.
Key Findings
According to the investigators, paclitaxel-based chemotherapy plus cemiplimab and fianlimab met graduation criteria across all biomarker signatures, with higher pathologic complete response rates than control therapy in all patients with ERBB2-negative disease (44% [95% confidence interval (CI) = 34%–53%] vs 21% [95% CI = 17%–25%]), triple-negative disease (53% [95% CI = 39%–67%] vs 29% [95% CI = 22%–36%]), and hormone receptor–positive/ERBB2-negative disease (36% [95% CI = 23%–49%] vs 14% [95% CI = 9%–19%]).
Adrenal insufficiency, including secondary adrenal insufficiency due to hypophysitis, was reported in 16 patients (21%), including 8 (11%) with grade 3 or 4 events; most cases occurred after immunotherapy had ended.
Among patients receiving paclitaxel-based chemotherapy plus cemiplimab and fianlimab, pathologic complete response rates were found to be substantially higher in those with immune signature–positive vs –negative status, at 83% vs 28% in triple-negative disease and 91% vs 28% in hormone receptor–positive/ERBB2-negative disease. Differences were more modest in the control group, the investigators wrote.
Insights and Opportunities
“In this randomized clinical trial, the addition of cemiplimab and fianlimab to standard neoadjuvant chemotherapy resulted in impressive pathologic complete response rates in all subsets of patients with early-stage, high-risk ERBB2-negative breast cancer, most notably in those with the immune-positive signature status,” the investigators concluded. “However, this combination was associated with concerning rates of immune-related adverse events, including adrenal insufficiency and late development of diabetes.”
They added, “The findings from our trial underscore the importance that immune-related adverse events can occur well after the completion of therapy; therefore, patients should be monitored closely during the postoperative period.”
The investigators further noted that future research should focus on identifying patients with hormone receptor–positive/ERBB2-negative disease or triple-negative breast cancer who are most likely to benefit from immunotherapy and for whom the risk of toxic effects may be more acceptable. They also suggested that emerging approaches targeting both PD-L1 and LAG-3, such as bispecific antibodies currently in development, could potentially achieve comparable efficacy with improved tolerability.
Claudine Isaacs, MD, of Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, is the corresponding author of the article in JAMA Oncology.
Disclosure: The study was supported by the National Cancer Institute, along with additional support from the Quantum Leap Healthcare Collaborative, Foundation for the National Institutes of Health, Safeway Foundation, William K. Bowes, Jr. Foundation, Give Breast Cancer the Boot, and the Breast Cancer Research Foundation. Drug manufacturers Regeneron and Amgen provided funding and study drugs but had no role in study design, data collection or analysis, or manuscript preparation. For full disclosures of the study authors, visit jamanetwork.com.
